Epstein-Barr virus (EBV) immortalizes B cells and is associated with human malignancies including Burkitt's lymphoma, nasopharyngeal carcinoma, gastric carcinoma, Hodgkin's disease and lymphoproliferative disease in immunosuppressed patients such as AIDS patients and organ and bone marrow transplant patients. Primary infection by EBV may cause infectious mononucleosis in young adults. Primary infection leads to a proliferative expansion of the infected B cells. This is followed by the establishment of life-long persistence in which the EBV genome resides in resting B cells. Lytic viral replication occurs in the oropharynx and results in virus shedding into the saliva. Different patterns of EBV latency gene expression are seen in latently infected resting B cells and in EBV associated tumors. This application addresses factors that may regulate these expression patterns and contribute to the different aspects of EBV pathogenesis. EBV replication is necessary for virus spread and Zta is a key regulator of the EBV lytic cycle. Zta not only regulates EBV lytic DNA replication but may also influence the maintainance of latent infection. The Specific Aims are: (Aim 1). To characterize the role of Zta in replication of the EBV origin of lytic replication, orilyt. Transfection assays will be used to analyse the role of Zta in the formation of replication compartments, to analyze the relative contributions of Zta's transcriptional and replication activities to orilyt activation and to relate Zta mediated regulation of the cell cycle to Zta replication function. (Aim 2). To evaluate the contribution of the JAK-STAT signaling pathway to the regulation of EBV latency gene expression in in vivo latency and tumorigenesis. STAT regulation of individual EBV latency promoters will be examined in transient assays. The role of activated STATs and Zta expression in the maintainance of EBV positive epithelial tumor cell lines in culture will be pursued and negative regulation of the EBV lytic cycle by STATs will be examined. (Aim 3). A role for EBNA-1 in the regulation of EBV latency gene expression will be evaluated.